Recently, attempts have been frequently made to apply enzymes and physiologically active proteins as drugs for treating various diseases including cancer, inflammation and hereditary enzyme deficiency.
However, many of these enzymes and physiologically active proteins are heterogenic to living organisms. Thus the administration of these compounds as such to an organism would cause a problem of immunogenicity or deteriorate the stability in vivo. When such a compound is to be formulated into a medicine, therefore, it is required to relieve an anaphylatic reaction and to improve the prolonged drug effect.
Furthermore, attempts have been made to produce these proteins in a large amount through genetic engineering techniques. However, proteins produced by genetic engineering suffer from a problem of the deficiency of a sugar chain, which seriously affects the stability in vivo.
Accordingly, there has been proposed to modify an enzyme or a physiologically active protein with various synthetic polymers or polysaccharides so as to pharmacologically improve the stability thereof. Examples of the synthetic polymers employed therefor include poly-L-aspartic acid (M. Okada, A. Matsushima, A. Katsuhata, T. Aoyama, T. Ando and Y. Inada: Int. Archs Allerlrgy Appl. Immun. 76, 79-81 (1985)) and derivatives thereof, poly-D- or -L-lysine, D-glutamic acid/D-lysine copolymer (F. T. Liu and D. H. Katz: Proc. Natl. Acad. Sci. USA, 76, 1430-1434 (1979)), polyvinyl alcohol pyran copolymer, polyethylene glycol and derivatives thereof and styrene/maleic acid copolymer (H. Maeda, M. Ueda, T. Morinaga and T. Matsumoto: J. Med. Chem., 28, 455-461 (1985)). Examples of the polysaccharides include agarose, carboxymethyl cellulose, dextran (T. P. King, L. Kochoumian, K. Ishizaka, L. Kichtenstein, P. S. Norman: Arch. Biochem. Biophys., 169, 464-473 (1975)), pullulan (M. Usui and T. Matsuhashi: J. Immunol., 122, 1266-1272 (1979) and N. Matsuhashi: Genkansa no Jikken Dobutsu Moderu (Experimental Animal Model for Hyposensitization), ed. by S. Kobayashi et al., Genkansa Ryoho no Kiso to Rinsho (Bases and Clinical Application of Hyposensitization Therapy), 4-11, Chugai Igakusho (1982)) and lipopolysaccharide.
On the other hand, U.S. Pat. No. 4,585,754 proposes a stabilized protein which is obtained by reacting a protein such as superoxide dismutase or insulin with chondroitin sulfate in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. However, the protein thus obtained is in the form of a complicated polymer involving a polymer of the protein per se, since plural carboxyl groups in aspartic acid or glutamic acid contained in the protein are activated by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, respectively. Thus, this product should be further improved from the viewpoint of the pharmacological effect of the unmodified superoxide dismutase or insulin as a monomer.